Abstract
The Coxsackievirus and adenovirus receptor (CAR) is essential for normal electrical conductance in the heart, but its role in the postnatal brain is largely unknown. Using brain specific CAR knockout mice (KO), we discovered an unexpected role of CAR in neuronal communication. This includes increased basic synaptic transmission at hippocampal Schaffer collaterals, resistance to fatigue, and enhanced long-term potentiation. Spontaneous neurotransmitter release and speed of endocytosis are increased in KOs, accompanied by increased expression of the exocytosis associated calcium sensor synaptotagmin 2. Using proximity proteomics and binding studies, we link CAR to the exocytosis machinery as it associates with syntenin and synaptobrevin/VAMP2 at the synapse. Increased synaptic function does not cause adverse effects in KO mice, as behavior and learning are unaffected. Thus, unlike the connexin-dependent suppression of atrioventricular conduction in the cardiac knockout, communication in the CAR deficient brain is improved, suggesting a role for CAR in presynaptic processes.
Highlights
Synaptic transmission requires the formation and alignment of pre- and postsynaptic structures, which depends on diverse cell adhesion proteins[1]
Based on the role of CAR in cardiac electro-conduction, the parallel perinatal regulation of CAR expression in heart and brain, and the available in vitro data on CAR’s neuronal functions[13,20,24], we asked if the residual CAR expression in the adult brain is required for normal neuronal function, and which pathways might be affected by CAR in vivo
CAR mRNA levels were reduced ~10-fold in the 7-day-old brain specific knockout as compared to CARlox/lox CamKIIαCre− control mice (CON), which carry the floxed allele but lack the cre transgene and express normal levels of CAR (Fig. 1A)
Summary
Synaptic transmission requires the formation and alignment of pre- and postsynaptic structures, which depends on diverse cell adhesion proteins[1] During embryonic development, these proteins mediate neuronal migration and neurite outgrowth[2,3]. These proteins mediate neuronal migration and neurite outgrowth[2,3] Their role in synaptic plasticity and transmission extends to the adult brain, where homo- or heterophilic interactions provide a mechanical link between neurons, but regulate signal transduction[4]. Molecular and cell based studies have indicated a role of CAR in neuronal signaling: The two extracellular Ig-domains of CAR mediate homo- and heterodimerization and interact with extracellular matrix proteins, which affects neurite outgrowth in vitro[20]. Based on the role of CAR in cardiac electro-conduction, the parallel perinatal regulation of CAR expression in heart and brain, and the available in vitro data on CAR’s neuronal functions[13,20,24], we asked if the residual CAR expression in the adult brain is required for normal neuronal function, and which pathways might be affected by CAR in vivo
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